This invention relates to novel fused tricyclic compounds that are inhibitors of mammalian Target of Rapamycin (mTOR) kinase, which is also known as FRAP, RAFT, RAPT or SEP, and are useful in the treatment of cellular proliferative diseases, for example cancer and other proliferative disorders.
The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation and plays a gatekeeper role in the control of cell cycle progression. mTOR mediates mitgenic signals from P13K/AKT through to the downstream targets S6K1 and 4E-BP1 and to Ser 473 on AKT. Recently, it has been shown that mTOR exists in two complexes. Rator-mTOR complex (mTORC1) is a rapamycin-sensitive complex that phosphorylates S6K1 (ribosomal S6 kinase 1) and 4E-BP1 (eukaryotic translation initiation factor 4E-binding protein). Rictor-mTOR complex (mTORC2) is a rapamycin-insensitive complex that phosphorlates AKT. Although the precise mechanism by which rapamycin inhibitis mTOR function is not well understood, rapamycin partially inhibits mTOR function through mTORC1. Since mTORC2 is involved in the regulation of cell survival and actin cytoskeletal organization in a rapamycin-independent manner, complete inhibition of mTOR function through inhibition of both mTORC1 and mTORC2 may lead to a broader spectrum antitumor activity and/or better efficacy than through inhibition of mTORC1 alone.
There exists a need in the art for small-molecule compounds having desirable physiochemical properties that are useful for treating cancer and other proliferative disorders. Specifically, there exists a need for small molecule inhibitors of mTOR kinase that block signaling through mTORC1 and mTORC2 for treating cancer and other cell proliferative diseases.